Arsov Ivica, Adebayo Adeola, Kucerova-Levisohn Martina, Haye Joanna, MacNeil Margaret, Papavasiliou F Nina, Yue Zhenyu, Ortiz Benjamin D
Department of Biology, York College, City University of New York, Jamaica, NY 11451, USA.
J Immunol. 2011 Feb 15;186(4):2201-9. doi: 10.4049/jimmunol.1002223. Epub 2011 Jan 14.
Autophagy is a highly regulated and evolutionarily conserved process of cellular self-digestion. Recent evidence suggests that this process plays an important role in regulating T cell homeostasis. In this study, we used Rag1(-/-) (recombination activating gene 1(-/-)) blastocyst complementation and in vitro embryonic stem cell differentiation to address the role of Beclin 1, one of the key autophagic proteins, in lymphocyte development. Beclin 1-deficient Rag1(-/-) chimeras displayed a dramatic reduction in thymic cellularity compared with control mice. Using embryonic stem cell differentiation in vitro, we found that the inability to maintain normal thymic cellularity is likely caused by impaired maintenance of thymocyte progenitors. Interestingly, despite drastically reduced thymocyte numbers, the peripheral T cell compartment of Beclin 1-deficient Rag1(-/-) chimeras is largely normal. Peripheral T cells displayed normal in vitro proliferation despite significantly reduced numbers of autophagosomes. In addition, these chimeras had greatly reduced numbers of early B cells in the bone marrow compared with controls. However, the peripheral B cell compartment was not dramatically impacted by Beclin 1 deficiency. Collectively, our results suggest that Beclin 1 is required for maintenance of undifferentiated/early lymphocyte progenitor populations. In contrast, Beclin 1 is largely dispensable for the initial generation and function of the peripheral T and B cell compartments. This indicates that normal lymphocyte development involves Beclin 1-dependent, early-stage and distinct, Beclin 1-independent, late-stage processes.
自噬是一种受到高度调控且在进化上保守的细胞自我消化过程。最近的证据表明，这一过程在调节T细胞稳态中发挥重要作用。在本研究中，我们利用Rag1(-/-)（重组激活基因1(-/-)）囊胚互补和体外胚胎干细胞分化来研究关键自噬蛋白之一Beclin 1在淋巴细胞发育中的作用。与对照小鼠相比，Beclin 1缺陷的Rag1(-/-)嵌合体的胸腺细胞数量显著减少。通过体外胚胎干细胞分化，我们发现无法维持正常胸腺细胞数量可能是由于胸腺细胞祖细胞的维持受损所致。有趣的是，尽管胸腺细胞数量大幅减少，但Beclin 1缺陷的Rag1(-/-)嵌合体的外周T细胞区室基本正常。尽管自噬体数量显著减少，但外周T细胞在体外仍表现出正常的增殖。此外，与对照相比，这些嵌合体骨髓中的早期B细胞数量大幅减少。然而，外周B细胞区室并未受到Beclin 1缺陷的显著影响。总体而言，我们的结果表明，Beclin 1是维持未分化/早期淋巴细胞祖细胞群体所必需的。相比之下，Beclin 1在外周T和B细胞区室的初始生成和功能中基本是可有可无的。这表明正常的淋巴细胞发育涉及Beclin 1依赖的早期阶段和独特的、Beclin 1不依赖的后期阶段。
